rs12210123

Variant names:

• chr6-70300398-A-G
• rs12210123
• NM_001851.6:c.89-12T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001851.6(COL9A1):​c.89-12T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 1,544,692 control chromosomes in the GnomAD database, including 26,920 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3338 hom., cov: 31)
  • Exomes 𝑓: 0.18 (23582 hom.)
• Consequence: COL9A1 NM_001851.6 intron
• Scores: Splicing: ADA: 0.005395
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.450
• Publications: 10 publications found

Genes affected

COL9A1 (HGNC:2217): (collagen type IX alpha 1 chain) This gene encodes one of the three alpha chains of type IX collagen, which is a minor (5-20%) collagen component of hyaline cartilage. Type IX collagen is usually found in tissues containing type II collagen, a fibrillar collagen. Studies in knockout mice have shown that synthesis of the alpha 1 chain is essential for assembly of type IX collagen molecules, a heterotrimeric molecule, and that lack of type IX collagen is associated with early onset osteoarthritis. Mutations in this gene are associated with osteoarthritis in humans, with multiple epiphyseal dysplasia, 6, a form of chondrodysplasia, and with Stickler syndrome, a disease characterized by ophthalmic, orofacial, articular, and auditory defects. Two transcript variants that encode different isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

COL9A1 Gene-Disease associations (from GenCC):

• Stickler syndrome, type 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• epiphyseal dysplasia, multiple, 6

  Inheritance: Unknown, AD, AR Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• multiple epiphyseal dysplasia due to collagen 9 anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive Stickler syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Stickler syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 6-70300398-A-G is Benign according to our data. Variant chr6-70300398-A-G is described in ClinVar as Benign. ClinVar VariationId is 258362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001851.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A1	NM_001851.6	MANE Select	c.89-12T>C		intron	N/A	NP_001842.3
	COL9A1	NM_001377291.1		c.89-12T>C		intron	N/A	NP_001364220.1	P20849-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A1	ENST00000357250.11	TSL:1 MANE Select	c.89-12T>C		intron	N/A	ENSP00000349790.6	P20849-1
	COL9A1	ENST00000370496.3	TSL:1	c.89-12T>C		intron	N/A	ENSP00000359527.3	P20849-3

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30603 AN: 151438 Hom.: 3336 Cov.: 31

Gnomad AFR AF: 0.271

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.142

Gnomad ASJ AF: 0.228

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.258

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.190

GnomAD2 exomes AF: 0.168 AC: 42203 AN: 251072 AF XY: 0.169

Gnomad AFR exome AF: 0.275

Gnomad AMR exome AF: 0.100

Gnomad ASJ exome AF: 0.222

Gnomad EAS exome AF: 0.000598

Gnomad FIN exome AF: 0.199

Gnomad NFE exome AF: 0.196

Gnomad OTH exome AF: 0.186

GnomAD4 exome AF: 0.178 AC: 248179 AN: 1393150 Hom.: 23582 Cov.: 24 AF XY: 0.178 AC XY: 123949 AN XY: 697348

African (AFR) AF: 0.284 AC: 9087 AN: 32028

American (AMR) AF: 0.106 AC: 4713 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 5639 AN: 25718

East Asian (EAS) AF: 0.000712 AC: 28 AN: 39322

South Asian (SAS) AF: 0.144 AC: 12253 AN: 84878

European-Finnish (FIN) AF: 0.201 AC: 10713 AN: 53320

Middle Eastern (MID) AF: 0.224 AC: 1262 AN: 5634

European-Non Finnish (NFE) AF: 0.185 AC: 194210 AN: 1049554

Other (OTH) AF: 0.177 AC: 10274 AN: 58070

GnomAD4 genome AF: 0.202 AC: 30611 AN: 151542 Hom.: 3338 Cov.: 31 AF XY: 0.199 AC XY: 14754 AN XY: 74058

African (AFR) AF: 0.271 AC: 11189 AN: 41290

American (AMR) AF: 0.142 AC: 2161 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 789 AN: 3464

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5184

South Asian (SAS) AF: 0.138 AC: 663 AN: 4808

European-Finnish (FIN) AF: 0.198 AC: 2051 AN: 10372

Middle Eastern (MID) AF: 0.267 AC: 78 AN: 292

European-Non Finnish (NFE) AF: 0.191 AC: 12977 AN: 67880

Other (OTH) AF: 0.189 AC: 398 AN: 2106

Alfa AF: 0.192 Hom.: 4299

Bravo AF: 0.202

Asia WGS AF: 0.0660 AC: 231 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	18
DANN	Benign	0.89
PhyloP100		0.45
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0054
dbscSNV1_RF	Benign	0.11
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12210123; hg19: chr6-71010101;